A Haptoglobin Exon Copy Number Variant Associates With HIV-Associated Neurocognitive Impairment in European and African-Descent Populations

Haimeng Bai,Donald R Franklin,William S Bush,Ronald J Ellis,Scott L Letendre,Todd Hulgan,Harpreet Kaur,Asha R Kallianpur

doi:10.3389/fgene.2021.756685

Abstract

A common two-exon deletion distinguishes the gene encoding the free hemoglobin capturing protein—haptoglobin (HP)–into two alleles: HP1 and HP2. To evaluate the impact of this copy number variant (CNV) on neurocognitive impairment (NCI) in people living with HIV, we imputed this variant in 432 European-descent (EUR) and 491 African-descent (AFR) participants from the CNS HIV Antiretroviral Therapy Effects Research Study using an optimized imputation pipeline and evaluated its associations with NCI. At baseline, in AFR, the HP2 allele decreased the odds of NCI (defined by a global deficit score, GDS, ; Odds Ratio, OR = 0.584, p = 0.022). However, in EUR, HP2 increased the odds (OR = 2.081, p = 0.040) of NCI suggesting a detrimental effect. These effects were extended to longitudinal analyses using repeated measurements where the protective effect of the HP2 allele in AFR became marginally significant (p = 0.054) and in EUR the detrimental effect increased in significance (p = 0.037). In EUR, the HP2 allele slightly reduced the risk of NCI over time (OR = 0.028 per allele per year, p = 0.024). Further analyses of cognitive domain-specific impairment revealed that the HP-NCI effect was based on changes in learning, speed of information processing, and verbal domains over time differing by ancestry groups. Overall, these findings suggest that these functional HP CNV alleles influence the likelihood of NCI and contribute to changes in neurocognitive function over time in people living with HIV.

Highlights

Neurocognitive disorders have long been complications of human immunodeficiency virus (HIV) infection
EUR people living with HIV (PLWH) who have HP2-2 have higher HIV viral load (Delanghe et al, 1998; MacKellar and Vigerust, 2016). It remains unclear whether the HP copy number variant (CNV) is associated with neurocognitive impairment (NCI) in PLWH, including individuals receiving suppressive Combination antiretroviral therapy (cART). We address this question by imputing HP genotypes for the AFR and EUR participants in the central nervous system (CNS) HIV Antiretroviral Therapy Effects Research (CHARTER) Study, a large, observational HIV cohort with comprehensive neurocognitive assessments and previously measured cerebrospinal fluid (CSF) HP protein levels, and evaluating the associations between HP genotype and NCI at baseline and over time
The quality control (QC) and basic data cleaning pipeline used for CHARTER genomic data was published previously (Jia et al, 2017); here we describe the additional QC work that was conducted for HP imputation

Summary

Introduction

Neurocognitive disorders have long been complications of HIV infection. Combination antiretroviral therapy (cART) has reduced morbidity and mortality in people living with HIV (PLWH) and remarkably prolonged their life expectancy (Grant et al, 2014; Watkins and Treisman, 2015). As PLWH age, neurologic complications like HIV-associated neurocognitive disorders (HAND) have become increasingly prevalent in both African-descent (AFR) and Europeandescent (EUR) populations (Antinori et al, 2007; Heaton et al, 2010; Grant et al, 2014). Ranked according to the severity of neurocognitive impairment (NCI), as established by Frascati criteria, the most severe yet uncommon form of HAND is HIV-associated dementia (HAD), followed by milder forms, including mild neurocognitive disorder (MND) and asymptomatic neurocognitive impairment (ANI) (Grant et al, 2014). NCI is the defining feature of HAND It affects one or more of seven cognitive function domains, including verbal fluency, speed of information processing (SIP), learning, memory, motor function, attention and working memory, and executive function (Woods et al, 2004). The Global Deficit Score (GDS) represents an overall measure of neurocognitive performance based on a comprehensive neuropsychological test battery, and is widely used to rate HIV-associated NCI (Blackstone et al, 2012). It was previously shown that defining NCI as GDS P0.5 yields the optimal balance between sensitivity and specificity (Blackstone et al, 2012)

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